tbuckley/cabot-search huggingface dataset:
Abstract 4296: Fast de novo antibody structure prediction with atomic accuracy
Authors: Yining Wang, Xumeng Gong, Shaochuan Li, Bing Yang, Yiwu Sun, Yujie Luo, Hui Li, Le Song
Journal: Cancer Research (2023)

Abstract Background: In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2 (AF2), a breakthrough in the field of structural biology, provides a solution to this protein structure prediction problem by learning a deep learning model. However, the computational efficiency and undesirable prediction accuracy on antibody, especially on the complementarity-determining regions limit its applications in de novo antibody design. Methods: To learn informative representation of antibodies, we trained a deep antibody language model (ALM) on curated sequences from observed antibody space database via a well-designed transformer model. We also developed a novel model named xTrimoABFold++ to predict antibody structure from antibody sequence only based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame aligned point loss. Results: xTrimoABFold++ outperforms AF2 and OmegaFold, HelixFold-Single with 30+% improvement on RMSD. Also, it is 151 times faster than AF2 and predicts antibody structure in atomic accuracy within 20 seconds. In recently released antibodies, for example, cemiplimab of PD-1 (PDB: 7WVM) and cross-neutralizing antibody 6D6 of SARS-CoV-2 (PDB: 7EAN), the RMSD of xTrimoABFold++ are 0.344 and 0.389 respectively. Conclusion: To the best of our knowledge, xTrimoABFold++ achieved the state-of-the-art in antibody structure prediction. Its improvement on both accuracy and efficiency makes it a valuable tool for de novo antibody design, and could make further improvement in immuno-theory. Experimental results on immune antibody dataset with 95% confidence interval. Method RMSD TMScore GDTTS GDTHA AlphaFold2 3.1254 ± 0.1410 0.8385 ± 0.0055 0.7948 ± 0.0057 0.6548 ± 0.0063 OmegaFold 3.2610 ± 0.1463 0.8384 ± 0.0057 0.7925 ± 0.0059 0.6586 ± 0.0063 HelixFold-Single 2.9648 ± 0.0997 0.8328 ± 0.0055 0.7805 ± 0.0057 0.6225 ± 0.0060 ESMFold 3.1549 ± 0.0067 0.8390 ± 0.0003 0.7952 ± 0.0003 0.6551 ± 0.0003 xTrimoABFold++ 1.9594 ± 0.0805 0.8986 ± 0.0052 0.8694 ± 0.0057 0.7456 ± 0.0066 Citation Format: Yining Wang, Xumeng Gong, Shaochuan Li, Bing Yang, Yiwu Sun, Yujie Luo, Hui Li, Le Song. Fast de novo antibody structure prediction with atomic accuracy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4296.
Abstract 2551: CASC4 drives anoikis resistance in high grade serous ovarian cancer through recycling of EGFR
Authors: Jaidev Bapat, Lindsay W. Brubaker, Zachary L. Watson, Tomomi M. Yamamoto, Benjamin G. Bitler
Journal: Cancer Research (2023)

Abstract Introduction: Ovarian cancer is the deadliest gynecological malignancy, and accounts for over 150,000 deaths per year worldwide. The high grade serous ovarian cancer (HGSOC) subtype accounts for almost 60% of ovarian cancers and is the deadliest. HGSOC originates in the fimbria of the fallopian tube and disseminates through the peritoneal cavity. Survival of tumor cells in the peritoneal fluid requires cells to resist anoikis (anchorage-independent apoptosis). CRISPR/Cas9 and transcriptomic screens identified the Golgi protein CASC4 (GOLM2, H63) as a “driver” of anoikis resistance. As CASC4 is highly uncharacterized in literature, we sought to determine how CASC4 confers anoikis resistance to HGSOC cells. Methods: Mining of publicly available ovarian cancer datasets (TCGA) showed that CASC4 is associated with worse clinical outcomes, such as worse overall survival and increased resistance to platinum-based chemotherapies. For experiments, we used HGSOC cell lines PEO1, CaOV3, and OVCAR3 with shRNA-mediated CASC4 knockdowns (CASC4 KD), cultured in forced suspension. Results: Culturing cells in suspension, to recapitulate the peritoneal fluid environment in vitro, showed that CASC4 KD hampers cell proliferation and colony formation ability, and increases apoptosis. Additionally, a Reverse Phase Protein Assay (RPPA) showed that CASC4 KD results in significant changes in proteins known to be localized to the cell surface or secreted, including decreased protein levels of the receptor tyrosine kinase (RTK) Epidermal Growth Factor Receptor (EGFR), an initiator of several oncogenic signaling pathways. A paralog of CASC4, GOLM1, is known to drive hepatocellular carcinoma through various mechanisms, such as the recycling of internalized RTKs, including EGFR. Indeed, our experiments showed that CASC4 KD in ovarian cancer cells leads to decreased EGFR levels and decreased EGFR recycling. Conclusion: Knocking down CASC4 results in decreased survivability in suspension, decreased EGFR levels at the plasma membrane, and decreased recycling of EGFR. Further elucidating mechanisms of CASC4-dependent anoikis resistance could lead to the development of novel therapeutic approaches, such as inhibitory peptides, and may assist in developing newer biomarkers for predicting ovarian cancer malignancy. Citation Format: Jaidev Bapat, Lindsay W. Brubaker, Zachary L. Watson, Tomomi M. Yamamoto, Benjamin G. Bitler. CASC4 drives anoikis resistance in high grade serous ovarian cancer through recycling of EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2551.
Abstract 6107: Novel roles for AMBRA1 in regulating DNA double-strand breaks
Authors: Yuning Jiang, Tarek Abbas
Journal: Cancer Research (2023)

Abstract AMBRA1 (Activating Molecule in Beclin-1-Regulated Autophagy) is a tumor suppressor protein whose expression is downregulated in several human malignancies. AMBRA1 was recently found to function as a substrate receptor for the cullin-4-based ubiquitin ligase (CRL4AMBRA1) that promotes the ubiquitin-dependent proteolysis of D-type cyclins (cyclin D1, D2 and D3); this serves to guard against premature S-phase entry and replication stress, providing a potential mechanism for its tumor suppressive activity. Cyclin D1 protein, which is stabilized, along with cyclin D2 and D3, in AMBRA1-deficient cells, has been shown to promote homologous recombination (HR) repair of DNA double-strand breaks (DSBs), suggesting that AMBRA1 may be additionally involved in the repair of DSBs. Using our recently published CRISPR-Cas9-based dual fluorescent reporter assay system, we show that while the loss of AMBRA1 increased D-type cyclins and Rb hyperphosphorylation as expected, it did, surprisingly, inhibit HR-mediated repair and stimulated error-free non-homologous end-joining (NHEJ), and that both of these new activities are independent of cyclin D1 or RB1. High-throughput sequencing of DSB repair junctions confirm these results and shows significant depletion of indels with reduction in microhomology-mediated end-joining in AMBRA1-deficient cells, suggesting that AMBRA1 plays a role in promoting resection at DSBs. In support of this hypothesis, we found that the loss of AMBRA1 reduces RAD51 recruitment to DSBs in cells exposed to ionizing radiation. Consistent with its role in promoting HR, we found that AMBRA1-deficient cells are significantly more sensitive to PARP inhibitors compared to AMBRA1-proficient cells. In summary, we show that AMBRA1 is a novel regulator of DSBs, and that its downregulation in cancer cells and tumors render cancer cells susceptible to inhibition by PARP inhibitors. Citation Format: Yuning Jiang, Tarek Abbas. Novel roles for AMBRA1 in regulating DNA double-strand breaks. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6107.
Abstract 606: <i>Cis</i>-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function
Authors: Yunlong Zhao, Christine Caron, Ya-Yuan Chan, Calvin K. Lee, Xiaozheng Xu, Jack D. Bui, Enfu Hui
Journal: Cancer Research (2023)

Abstract Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cell immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in tumor-infiltrated T cells is activated in the absence of corresponding ligands on cancer. In current dogma, the T cell CD28 can be activated in trans by CD80 (B7-1) or CD86 (B7-2) expressed on professional antigen presenting cells (APCs) enriched in secondary lymphoid organs. Notably, besides professional APCs, B7 ligands are also displayed by T cells, but their functions are unclear. Here we report that B7 ligands expressed on T cells interact with CD28 in cis at membrane invaginations of the immunological synapse, as a result of phosphoinositide-3-kinase (PI3K) mediated membrane remodeling. Cis-B7:CD28 interactions triggered CD28 signaling through protein-kinase-C-theta (PKCθ) and promoted T cell survival, migration and cytokine production. In a B7 deficient tumor model grafted with primed CD8+ T cells, blockade of T cell intrinsic B7:CD28 interactions accelerated tumor growth and decreased intratumoral T cells. Thus, B7 ligands on T cells can evoke cell autonomous CD28 costimulation in cis in peripheral tissues, suggesting cis-signaling as a general mechanism for boosting T cell functionality. Citation Format: Yunlong Zhao, Christine Caron, Ya-Yuan Chan, Calvin K. Lee, Xiaozheng Xu, Jack D. Bui, Enfu Hui. Cis-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 606.
Abstract 1288: NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals
Authors: Yiwei Gu, Xiuping Huang, Qing Ye, Qing-Bai She
Journal: Cancer Research (2023)

Abstract Neuropilin-1 (NRP1) is a transmembrane glycoprotein that acts as a critical co-receptor for tyrosine kinase receptors in growth factor signaling in both physiological and pathological context. The characterization of the NRP1 variants generated by alternative splicing mechanisms has provided profound insights into our understanding of the regulation of NRP1 function in cancer growth, angiogenesis, invasion and metastasis as well as for the modulation of therapeutic outcomes. Here, we identified a novel human NRP1 splice variant resulting from the skipping of exon 4 (NRP1-ΔE4) in colorectal cancer (CRC). We found that NRP1-ΔE4 was largely expressed in CRC and significantly correlated with CRC progression. Furthermore, NRP1-ΔE4 exhibited increased endocytosis/recycling activity via secreted exosomes and decreased levels of degradation, leading to accumulation on endosomes. In addition, NRP1-ΔE4 enhanced interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provided persistent endosomal signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking exosome secretion, endocytosis or endosomal Met/β1-integrin/FAK signaling using genetic and pharmacological approaches profoundly inhibited the oncogenic effects of NRP1-ΔE4. Taken together, these findings reveal a unique function of NRP1-ΔE4 in the regulation of endocytic trafficking for CRC cell dissemination. Citation Format: Yiwei Gu, Xiuping Huang, Qing Ye, Qing-Bai She. NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1288.
Abstract 121: In situ mutational mapping of tumor cells and tissues at subcellular resolution
Authors: Jessica Östlin, Debashish Chitnis, Mimmi Olofsson, Iván Hernández-Neuta, Malte Kuhnemund
Journal: Cancer Research (2023)

Abstract In situ techniques enable studying cells and tissues within their cellular context. This is of great importance in cancer, often displaying genetic and phenotypic heterogeneity with distinct subclones harboring different capacity to grow and spread. It was recently shown that by spatially mapping dozens of mutations within tumor tissues, tumor evolution and microenvironmental impact could be studied at the subclonal level (1). We have developed an in situ technique that spatially maps multiple expressed mutations simultaneously at subcellular resolution. The technique is based on single-nucleotide discriminating probes hybridized to mRNA. Correctly hybridized probes get ligated, amplified by rolling circle amplification, and decoded on our Xenium In situ platform. The technique was validated in well characterized cell lines, targeting multiple single nucleotide variants of the KRAS codons 12 and 13. As a proof of concept, we then applied the technique on FFPE breast tumor tissue sections that were previously characterized by targeted NGS onco-gene panels on extracted tumor DNA. In addition to the 280 plex Xenium Human Breast Gene Expression Panel, we targeted several mutations in situ and successfully mapped their spatial distribution in the tumor tissue sections. In summary, we demonstrate that the Xenium In Situ technology can spatially resolve the genetic and phenotypic landscape of breast tumors. The technology will enable researchers to unravel tumor evolution, growth and spread as well as the microenvironmental impact in detail, potentially refining patient stratification and treatment decisions. Citation Format: Jessica Östlin, Debashish Chitnis, Mimmi Olofsson, Iván Hernández-Neuta, Malte Kuhnemund. In situ mutational mapping of tumor cells and tissues at subcellular resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 121.
Abstract 6069: Genomic and transcriptomic characterization of medullary thyroid cancer
Authors: Seong Eun Lee, Seongyeol Park, Shinae Yi, Joonoh Lim, Na Rae Choi, JungHak Kwak, June-Young Koh, Boram Yi, Jaemo Koo, Jae Won Chang, Young Seok Ju, Bon Seok Koo, Jin Man Kim, Young Joo Park, Minho Shong, Eun Kyung Lee, Jae Kyung Won, Yea Eun Kang, Kyu Eun Lee
Journal: Cancer Research (2023)

Abstract Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy derived from the parafollicular C cells of thyroid gland. It features relatively aggressive biologic behavior among thyroid cancers, but its genomic landscape has not yet been fully explored. Here, we conducted multi-omics data (whole genome sequencing (WGS), and bulk (bulk RNA-seq) or single nucleus RNA sequencing (snRNA-seq)) on ​​MTC, and found genetic characteristics of MTC and a new gene signature predicting aggressiveness of tumors. WGS was performed for 35 pairs of tumor specimens and normal thyroid tissues from 30 patients. And bulk RNA-seq for 59 samples (20 normal thyroid tissues, 26 primary MTCs, 9 recurred lymph nodes, and 4 metastatic lymph nodes) and snRNA-seq for 3 primary MTCs, and 2 recurred/metastatic lymph nodes were also performed. In WGS results, we verified driver mutations, including RET, RAS, and BRAF. Four patients were classified as germline RET mutations based on familial history. Somatic RET M918T mutations were occurred in 8 patients, 9 patients were observed other RET mutations. Also, we observed other somatic mutations such as HRAS and BRAF. Seven patients occurred somatic HRAS mutations (Q61L, Q61R, G13R, A11 and G15), and somatic BRAF mutations (G469A, K601E) were observed in two patients. We found broad-level copy-number alterations in ~50% of patients, and we also found a patient who shows whole-genome duplication. The copy-number alteration was associated with aggressive phenotype in MTC. In addition, we found complex rearrangements such as microhomology-mediated break-induced replication in five patients. Interestingly, we found intra-tumoral heterogeneity of several genes related to C cell differentiation through snRNA-seq analysis by comparing clusters of tumor cells. Using the genes, we calculated the C cell differentiation score of the samples with bulk RNA-seq by GSVA algorithm. This score was related to poor clinical characteristics such as recurrence. In conclusion, multi-omics profiling of MTC reveals that copy number alterations and C cell differentiation status are the important biomarkers for cancer aggressiveness. Citation Format: Seong Eun Lee, Seongyeol Park, Shinae Yi, Joonoh Lim, Na Rae Choi, JungHak Kwak, June-Young Koh, Boram Yi, Jaemo Koo, Jae Won Chang, Young Seok Ju, Bon Seok Koo, Jin Man Kim, Young Joo Park, Minho Shong, Eun Kyung Lee, Jae Kyung Won, Yea Eun Kang, Kyu Eun Lee. Genomic and transcriptomic characterization of medullary thyroid cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6069.
Abstract 1688: Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer
Authors: Ryuichi Morita, Takeshi Ishikawa, Shinya Matsumura, Tomoki Sakakida, Juichiro Yoshida, Toshifumi Doi, Ryohei Hirose, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiko Uchiyama, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Yoshito Itoh
Journal: Cancer Research (2023)

Abstract Introduction: V-ATPase is highly expressed in cancer cells and has been shown to be involved in the transformation of normal cells into cancer cells, invasion of tissues, survival of cancer cells, and the formation of drug resistance. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been shown to enhance the efficacy of chemotherapy in some cancers. Material and Method: We investigated the effect of proton pump inhibitors on esophageal squamous cell carcinoma, one of the major causes of cancer mortality in Japan. First, three PPIs at various concentrations (lansoprazole, esomeprazole, and bonoprazan) and pyrimidine fluoride (5-FU), a key drug in chemotherapy for esophageal cancer, were used as basic medical agents. Human esophageal squamous cell lines, KYSE50 and KYSE70, were prepared and treated with the above drugs, and cell viability assays were performed using Cell Counting Kit 8 for 72 hours. We then performed a retrospective clinical study of 40 patients with clinical stage IV esophageal squamous cell carcinoma treated with the drugs at Kyoto Prefectural University of Medicine Hospital in Japan. Result: In cell survival assays, PPIs showed significantly enhanced cytotoxic effects of pyrimidine fluoride on all cell lines compared with those not treated with PPIs. Clinical data showed no difference in the incidence of treatment-related adverse events between the PPI and non-PPI groups. The response rate after two courses of chemotherapy was 66.7% in the PPI group and 40.9% in the non-PPI group (p=0.102). Kaplan-Meier analysis showed improved OS in patients treated with PPIs (log rank test p=0.032), and multivariate analysis showed that PPI use was associated with a more favorable OS (p=0.009,HR 0.33,95% CI 0.12-0.76 ). Conclusion: In the chemotherapy of esophageal squamous cell carcinoma, the use of PPIs may enhance the cytotoxic effect of the key drug, pyrimidine fluoride, while ensuring safety, and may lead to better therapeutic efficacy. Citation Format: Ryuichi Morita, Takeshi Ishikawa, Shinya Matsumura, Tomoki Sakakida, Juichiro Yoshida, Toshifumi Doi, Ryohei Hirose, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiko Uchiyama, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Yoshito Itoh. Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1688.
Abstract 276: Delineating the role of vesicular glutamate transporter SLC17A7 in osteosarcoma
Authors: Niveditha Nerlakanti, Jeremy McGuire, Ryan T. Bishop, Diana Yu, Damon R. Reed, Conor C. Lynch
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) frequently metastasizes to lung where it greatly contributes to patient mortality. Frustratingly, OS treatment options have remained static due to a paucity of strong pre-clinical evidence to motivate clinical trials. To identify therapeutic targets, we assessed a number of FDA approved therapies for their cytotoxic effects. We found that histone deacetylase (HDAC) inhibitors (panobinostat and romidepsin) limited OS viability at low nM and were highly effective for the treatment of lung metastatic disease in vivo. Although clinically approved, HDAC inhibitors have noted toxicities. Therefore, we next examined the potential mechanisms through which HDAC controlled OS growth. Gene expression analyses on romidepsin treated OS cells revealed key up and downregulated targets. We found that SLC17A7, a vesicular glutamate transporter, was highly and consistently induced in response to romidepsin (greater than 100 fold more than base line) across multiple OS cell lines. Functionally, SLC17A7 traps glutamate in cytoplasmic synaptic vesicles that are then released via exocytosis. Our data show that HDAC inhibition reduces glutamate secretion from OS cells while SLC17A7 overexpression significantly impaired OS viability. Further, we showed that the glutamate export inhibitor, riluzole, significantly impairs the OS growth in vitro and is highly effective for the treatment of lung metastatic OS in vivo. Taken together, we conclude that HDAC1/2 suppression of SLC17A7 ensures high cytoplasmic glutamate levels that can be leveraged for OS growth. We posit that targeting glutamate usage by OS cells using FDA approved inhibitors such as riluzole will be highly effective for the treatment of lung metastatic OS. Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Ryan T. Bishop, Diana Yu, Damon R. Reed, Conor C. Lynch. Delineating the role of vesicular glutamate transporter SLC17A7 in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 276.